Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy and the eighth leading cause of cancer-related deaths, worldwide. The 5-year survival rate is poor and has not substantially improved over the last 25 years. Moreover, there is no currently accepted screening test to detect premalignant forms or HNSCC in an early stage. Recently, a subset of HNSCC cancers have been found to be associated with oncogenic human papillomavirus (HPV) infections. However, there is no data evaluating whether detection of HPV in the oral cavity is a significant risk factor for subsequent development of HNSCC. The obvious question is whether HPV detection in the oral cavity can be used to identify individuals at highest risk for HPV- associated HNSCC. The most cost-effective approach is to utilize oral mouthwash specimens collected as part of large cohort studies that are followed-up for cancer. The American Cancer Society's Cancer Prevention Study II (CPS II) Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial collected a mouthwash specimen in more than 120,000 individuals for genomic DNA. We propose to pool the data from the two cohorts together and use these mouthwash samples in a nested case-control design (2 controls per case) to test the hypothesis that detection of HPV in the oral cavity is a biomarker for incident HNSCC. We will extract and test the mouthwash samples from all incident HNSCC (n=157) that have occurred in both cohort during follow-up (through 2007-08) and their respective matched controls. We will use 3 HPV tests developed in the Burk lab to detect the complete spectrum of HPV types found in the oral cavity. Data on known risk factors including tobacco and ethanol use will be used to adjust in the association analysis. PUBLIC HEALTH RELEVANCE: Head and neck squamous cell cancer (HNSCC) is the sixth most common malignancy and the eighth leading cause of cancer-related deaths, worldwide. However, there is no currently accepted screening test to detect premalignant or early stage HNSCC. Recently, a subset of HNSCC cancers was found to be associated with human papillomavirus (HPV) infection. We will take advantage of two large prospective cohorts, the American Cancer Society's Cancer Prevention Study II (CPS-II) and the NCI's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, combined they collected a mouthwash specimen in approximately 120,000 individuals whom are followed over time for development of cancer. We will determine whether HPV detection can predict the development of HNSCC. This project should provide fundamental information on the utility of oral HPV detection for the prevention and/or early detection of HNSCC. !